# Functional transition of CA2 pyramidal neurons along the proximodistal axis determines resonance frequency preference

## TL;DR

This study reveals that CA2 pyramidal neurons in the hippocampus show location-dependent frequency preferences along their proximodistal axis, influencing their role in network activity.

## Contribution

The study identifies a gradient of intrinsic properties in CA2 pyramidal neurons that determines their resonance frequency preference based on their position.

## Key findings

- Intrinsic membrane properties of CA2 pyramidal neurons vary gradually along the proximodistal axis.
- Distal neurons show a shift in resonance frequency preference from delta to lower theta ranges.
- Dendritic morphology and synaptic transmission do not correlate with neuronal position.

## Abstract

The hippocampal CA2 region has recently been linked to oscillatory activity, spatial navigation, and social behavior. Its predominant neuronal population, CA2 pyramidal neurons (CA2-PNs), critically contributes to hippocampal computations, yet the functional properties along the proximodistal extension of CA2 remain incompletely defined. In organotypic entorhino-hippocampal tissue cultures, we combined PCP4-based localization with single-cell reconstructions and whole-cell patch-clamp recordings to relate neuronal position to structure, synaptic transmission, and intrinsic properties in identified CA2-PNs. Dendritic morphology and spontaneous EPSCs did not correlate with position along the proximodistal axis. By contrast, intrinsic membrane properties, encompassing input resistance, rheobase and action potential metrics, varied gradually. Distal neurons exhibited a pronounced hyperpolarization-induced sag and subthreshold membrane resonance with a frequency preference shifting from delta frequency toward the lower theta range in a subset of cells along the proximodistal axis. Together, these findings reveal location-dependent frequency tuning in CA2 along the proximodistal axis and suggest that a gradient of intrinsic properties sets the conditions for input- and phase-specific recruitment of CA2 during hippocampal network activity.

The online version contains supplementary material available at 10.1038/s41598-026-39754-3.